Patent application WO 94/12478, the content of which is incorporated herein by reference, describes, inter alia, indole derivatives which inhibit blood platelet aggregation. Patent applications WO 01/00610 and WO 01/30774, the content of each of which is incorporated herein by reference, describe indole derivatives and benzimidazole derivatives which are able to modulate NFκB. NFκB is a heterodimeric transcription factor which is able to activate a large number of genes which encode, inter alia, proinflammatory cytokines such as IL-1, IL-2, TNFα or IL-6. NFκB is present in the cytosol of cells, where it is complexed with its naturally occurring inhibitor IκB. Stimulation of the cells, for example by cytokines, leads to the IκB being phosphorylated and subsequently broken down proteolytically. This proteolytic breakdown leads to the activation of NFκB, which then migrates into the nucleus of the cell, where it activates a large number of proinflammatory genes.
In diseases such as rheumatoid arthritis (in connection with inflammation), osteoarthritis, asthma, cardiac infarction, Alzheimer's diseases, diabetes Type II, “inflammatory bowel disease” or atherosclerosis, NFκB is activated to beyond the normal extent. The inhibition of NFκB is also of value in the treatment of cancer since it is used in such treatment on its own or to augment the cytostatic therapy. It has been demonstrated that pharmaceuticals such as gluocorticoids, salicylates or gold salts, which are used in the therapy of rheumatism, inhibit the NFκB-activating signal chain at various points or interfere directly with the transcription of the genes.
The first step in the abovementioned signal cascade is the breakdown of IκB. This phosphorylation is regulated by the specific IκB kinase. Thus far, no inhibitors are known which inhibit IκB kinase specifically.
The known inhibitors of IκB kinase frequently suffer from the disadvantage of lacking the specificity of inhibiting only one class of kinases. For example, most inhibitors of IκB kinase inhibit several different kinases at the same time because the structures of the catalytic domains of these kinases are similar. Consequently, the inhibitors act, in an undesirable manner, on many enzymes, including those which posses the vital function.
Patent application WO 01/30774, the content of which is incorporated herein by reference, has already described indole derivatives which are able to modulate NFκB and which exhibit a strong inhibitory effect on IκB kinase. However, the compounds which are disclosed in WO 01/30774, and are described in the examples, also exhibit a powerful inhibitory effect on other kinases, such as cAMP-dependent protein kinase, protein kinase C and casein kinase II. However, when their specificity is improved, some of these indole derivatives then exhibit a decrease in their ability to inhibit IκB kinase. Furthermore, the blood plasma level which can be achieved with the compounds disclosed in WO 01/30774 is insufficient for administering these derivatives orally.
In the endeavor to obtain effective compounds for treating rheumatoid arthritis (in association with inflammation), osteoarthritis, asthma, cardiac infarction, Alzheimer's diseases, cancer diseases (potentiation of treatments with cytotoxic agents) or atherosclerosis, it has now been found that the indole derivatives and benzimidazole derivatives according to the invention do not suffer from the abovementioned disadvantages. The indole derivatives and benzimidazole derivatives according to the invention are powerful inhibitors of IκB kinase, in this connection inhibiting kinases very selectively, and have a high blood plasma level following oral administration.